Dr. Gulley is interested in immunotherapy for epithelial malignancies with a focus on prostate cancer. As head of the Immunotherapy Section of the Genitourinary Malignancies Branch, he designs and conducts clinical trials based on promising laboratory findings. These innovative investigator-initiated studies involve the use of cancer vaccines and other immunostimulatory agents to modulate the immune response in cancer patients, and the addition of other strategies to enhance vaccine-mediated tumor killing. Dr. Gulley played a pivotal role in the clinical development of the prostate cancer vaccine Prostvac. Working with scientists in the laboratory, he developed the data needed to bring this logistically simple but immunologically sophisticated vaccine strategy, developed within the CCR, into phase I (first-in-human safety studies) and phase II (first test for clinical activity) clinical trials in prostate cancer. A multicenter, randomized phase II trial designed in collaboration with Dr. Gulley provided evidence of enhanced median overall survival (OS) (P = 0.0061) in patients with metastatic castration-resistant prostate cancer. A concurrent study run by Dr. Gulley at the CCR demonstrated that patients with greater PSA-specific T-cell responses showed a trend (P = 0.055) toward enhanced survival. Median OS was 26.6 months, with a greater apparent treatment benefit in patients with less aggressive or less advanced disease. Dr. Gulley and colleagues then met with the FDA and designed a phase III clinical trial that he subsequently shepherded through the process of gaining approvals from the Recombinant Advisory Committee, the FDA, and European Medicines Agency. This randomized, controlled phase III study, which he leads, is now fully enrolled with 1,297 patients and is expected to have OS results within 12 months. Other vaccines that Dr. Gulley has helped bring into the clinic in phase I or II studies include pox-viral platforms targeting CEA, MUC-1 and Brachyury; yeast platforms targeting CEA and Brachyury and there are plans for adenoviral vaccines targeting CEA, MUC-1, PSA, HPV and Brachyury. In 2016 the American Society of Clinical Oncology proclaimed immunotherapy as the top advance of the year, based in part on the rapid, profound, and durable responses seen with immune checkpoint inhibitors targeting PD-1 or PD-L1 proteins. (Immune checkpoints are molecules that modulate immune system signals. Many cancers use them to evade immune attack.) Dr. Gulley is the coordinating PI of an international trial of avelumab, an anti-PD-L1 antibody. This trial is a CCR collaboration with EMD Serono (who also partnered with Pfizer). Early data suggest robust activity for avelumab, with a side-effect profile similar to other agents. However, unlike other anti-PDL1 agents, avelumab is also capable of antibody-dependent cellular cytotoxicity (ADCC). Thus this antibody, in addition to directly enhancing the activity of T cells, can mediate ADCC which involves Natural Killer Cell-mediated killing of the tumors and immune cells that block T-cell function. Recent findings suggest that anti-PD-L1 agents that can mediate ADCC have improved activity over agents that cannot do so. Dr. Gulley's study has now enrolled over 1,600 patients (about 130 at the CCR), providing the initial safety and efficacy data that have led to six ongoing phase III clinical trials of avelumab, with more in the planning stages. The FDA recently gave avelumab breakthrough therapy designation for patients with advanced Merkel cell carcinoma. While the clinical response with immune checkpoint modulators has been profound, it is limited to patients who have an underlying T-cell inflamed tumor. The importance of determining the immune relevant cells and pathways operational within the tumor microenvironment is thus crucial to selecting patients who may benefit from immune checkpoint modulating therapies alone but more importantly the impact of therapies designed to generate a T-cell inflamed tumor and to guide rationale for potential combination studies. To further explore this we have established multiple strong collaborations with several groups (including surgeons, radiation oncologists, interventional radiologists, pathologists and various industry collaborations) who can assist us with obtaining and analyzing tissue before and after immunotherapy in various different disease settings. Furthermore, we are investigating a range of different modalities to induce T-cell inflammation which are in active clinical trials including vaccines, immunocytokines (e.g., NHL-IL12), and planned clinical trials (NK cells). As an extension of the importance of overcoming negative immune regulatory influences within the tumor microenvironment we also have brought into the clinic a first-in-class agent that targets both cell intrinsic (PDL-1) and cell extrinsic (TGF-beta) pathways and have seen that this is well tolerated and has preliminary evidence of activity. Finally, we also have an ongoing collaboration with Peter Choyke in the CCR Molecular Imaging Program on ways to image inflammation to allow a non-invasive, whole body measure of inflammation with preclinical feasibility studies complete and clinical studies planned.